Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation.

Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding NCWP's role is important since these opposing pathways act in concert to maintain homeostasis in healthy tissues. Our preliminary studies demonstrated that LiCl inhibited proliferation of primary cells derived from colorectal cancer (CRC). Since LiCl stimulates cell proliferation in normal tissues and NCWP suppresses it, the present study was designed to investigate the impact of NCWP components in LiCl-mediated effects. LiCl-mediated inhibition of CRC cell proliferation (p < 0.001) and increased apoptosis (p < 0.01) coincided with 23-fold increase (p < 0.025) in the expression of the NCWP ligand, Wnt9A. LiCl also suppressed ß-catenin mRNA (p < 0.03), total ß-catenin protein (p < 0.025) and the active form of ß-catenin. LiCl-mediated inhibition of CRC cell proliferation was partially reversed by IWP-2, and Wnt9A antibody. Recombinant Wnt9A protein emulated LiCl effects by suppressing ß-catenin protein (p < 0.001), inhibiting proliferation (p < 0.001) and increasing apoptosis (p < 0.03). This is the first study to demonstrate induction of a NCWP ligand, Wnt9A as part of a mechanism for LiCl-mediated suppression of CRC cell proliferation.

The relationship between baseline nutritional status with subsequent parenteral nutrition and clinical outcomes in cancer patients undergoing hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment option for selected patients with peritoneal carcinomatosis. This retrospective study investigated the relationship between baseline nutritional assessment with subsequent parenteral nutritional (PN) and clinical outcomes in cancer patients undergoing CRS and HIPEC. METHODS: A consecutive series of 60 patients undergoing CRS and HIPEC at our institution between January 2009 and May 2011. Subjective Global Assessment (SGA) was used to assess nutritional status. Patients were classified preoperatively as: well nourished (SGA-A), mildly-moderately malnourished (SGA-B), and severely malnourished (SGA-C). For PN, patients were divided into 2 groups: those who received PN (PN+) and those who did not receive PN (PN-). The primary outcomes of interest were length of stay (LOS), postoperative complications, ECOG performance status (PS) and survival. LOS was calculated as the number of days in the hospital post surgery. Performance status was measured on a scale of 0-4. Survival was calculated from the date of first visit to the date of death/last contact. RESULTS: Of 60 patients, 19 were males and 41 females. The mean age at presentation was 50.3 years. The most common cancer types were colorectal (n = 24) and gynecologic (n = 19) with the majority of patients (n = 47) treated previously before coming to our institution. 33 patients were SGA-A, 22 SGA-B and 5 SGA-C prior to surgery. Of a total of 60 patients, 31 received PN. Mean LOS for the entire cohort was 16.2 days (SD = 9.8). Mean LOS for preoperative SGA-A, SGA-B and SGA-C were 15.0, 15.2 and 27.8 days respectively (ANOVA p = 0.02). Overall incidence of complications was 26.7% (16/60). Complications were recorded in 9 of 33 (27.3%) preoperative SGA-A patients and 7 of 27 (25.9%) SGA-B + C patients (p = 0.91). The median overall survival was 17.5 months (95% CI = 13.0 to 22.1 months). Median survival for preoperative SGA-A and SGA-B + C cohorts was 22.4 and 10.4 months respectively (p = 0.006). CONCLUSIONS: The preoperative SGA predicts LOS and survival in cancer patients undergoing HIPEC. Future randomized clinical trials in this patient population should investigate the systematic provision of PN to all malnourished patients in the preoperative period for a minimum of 7-10 days with the continuation of PN in the postoperative period.

Prognostic value of changes in quality of life scores in prostate cancer.

BACKGROUND: Several studies in the oncology literature have demonstrated the prognostic value of baseline quality of life (QoL). We investigated whether changes in QoL could predict survival in prostate cancer patients. METHODS: We evaluated 250 prostate cancer patients treated at our institution between Jan 2001 and Dec 2009 who were available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment initiation using EORTC-QLQ-C30. Cox regression evaluated the prognostic significance of baseline and changes in QoL scores after adjusting for relevant clinical and demographic variables. RESULTS: Median overall survival was 89.1 months (95% CI: 56.5-121.7). Baseline QoL scale predictive of survival upon multivariate analysis was fatigue (p = 0.001). Associations between changes in QoL and survival, upon multivariate analysis, were observed for dyspnea and cognitive functioning. Every 10-point increase (worsening) in dyspnea was associated with a 16% increased risk of death (HR = 1.16; 95% CI = 1.02 to 1.30, p = 0.02), and every 10-point increase (improvement) in cognitive functioning was associated with a 24% decreased risk of death (HR = 0.76; 95% CI = 0.54 to 0.98, p = 0.04). CONCLUSIONS: This study provides preliminary evidence to indicate that prostate cancer patients with better baseline fatigue and patients whose dyspnea and cognitive functioning improves within 3 months of treatment are at a significantly decreased risk of mortality.

Predicting survival in prostate cancer: the role of quality of life assessment.

PURPOSE: While the use of quality of life (QoL) assessment has been increasing in clinical oncology, few studies have examined its prognostic significance in prostate cancer. We investigated the association between QoL at presentation and survival in prostate cancer. METHODS: We retrospectively reviewed 673 patients treated at two single-system cancer centers between January 2001 and December 2008. QoL was evaluated using EORTC-QLQ-C30. Patient survival was defined as the time interval between the date of first patient visit and the date of death/date of last contact. Univariate and multivariate Cox regression was performed to evaluate the prognostic significance of QoL. RESULTS: Mean age at presentation was 63.2 years. Patient stage of disease at diagnosis was I, 4; II, 464; III, 76; IV, 107; and 22 indeterminate. Median overall survival was 89.1 months (95% CI: 46.1-132.0). QoL scales predictive of survival upon univariate analysis were physical, role, emotional, social, fatigue, nausea/vomiting, pain, dyspnea, insomnia, loss of appetite, and constipation (p < 0.01 for all). Multivariate analyses found fatigue (p = 0.02) and constipation (p = 0.01) to be significantly associated with survival. CONCLUSIONS: Baseline QoL provides useful prognostic information in prostate cancer. These findings have important implications for patient stratification in clinical trials and may aid decision making in clinical practice.

Quality of life assessment as a predictor of survival in non-small cell lung cancer.

BACKGROUND: There are conflicting and inconsistent results in the literature on the prognostic role of quality of life (QoL) in cancer. We investigated whether QoL at admission could predict survival in lung cancer patients. METHODS: The study population consisted of 1194 non-small cell lung cancer patients treated at our institution between Jan 2001 and Dec 2008. QoL was evaluated using EORTC-QLQ-C30 prior to initiation of treatment. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression evaluated the prognostic significance of QoL. RESULTS: Mean age at presentation was 58.3 years. There were 605 newly diagnosed and 589 previously treated patients; 601 males and 593 females. Stage of disease at diagnosis was I, 100; II, 63; III, 348; IV, 656; and 27 indeterminate. Upon multivariate analyses, global QoL as well as physical function predicted patient survival in the entire study population. Every 10-point increase in physical function was associated with a 10% increase in survival (95% CI = 6% to 14%, p < 0.001). Similarly, every 10-point increase in global QoL was associated with a 9% increase in survival (95% CI = 6% to 11%, p < 0.001). Furthermore, physical function, nausea/vomiting, insomnia, and diarrhea (p < 0.05 for all) in newly diagnosed patients, but only physical function (p < 0.001) in previously treated patients were predictive of survival. CONCLUSIONS: Baseline global QoL and physical function provide useful prognostic information in non-small cell lung cancer patients.

The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer.

BACKGROUND: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer. METHODS: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months). RESULTS: We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health/Function domain, and not others, such as EORTC QLQ C30 Physical Domain. CONCLUSIONS: These data suggest the testable possibility that behavioral, hormonal and/or light-based strategies to improve circadian organization may help patients suffering from advanced lung cancer to feel and function better.

Can changes in health related quality of life scores predict survival in stages III and IV colorectal cancer?

BACKGROUND: Several studies have demonstrated the predictive significance on survival of baseline quality of life (QoL) in colorectal cancer (CRC) with little information on the impact of changes in QoL scores on prognosis in CRC. We investigated whether changes in QoL during treatment could predict survival in CRC. METHODS: We evaluated 396 stages III-IV CRC patients available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment using EORTC QLQ-C30. Cox regression evaluated the prognostic significance of baseline, 3-month and changes in QoL scores after adjusting for age, gender and stage at diagnosis. RESULTS: After adjusting for covariates, every 10-point increase in both baseline appetite loss and global QoL score was associated with a 7% increased risk of death with HR = 1.07 (95% CI, 1.01-1.14; P = 0.02) and (HR = 0.93 (95% CI, 0.87-0.98; P = 0.01) respectively. A lower risk of death was associated with a 10-point improvement in physical function at 3 months (HR, 0.86; 95% CI, 0.78-0.94; P = 0.001). Surprisingly, a higher risk of death was associated with a 10-point improvement in social function at 3 months (HR, 1.08; 95% CI, 1.02-1.13; P = 0.008). CONCLUSIONS: This study provides preliminary evidence to indicate that CRC patients whose physical function improves within 3 months of treatment have a significantly increased probability of survival. These findings should be used in clinical practice to systematically address QoL-related problems of CRC patients throughout their treatment course.

Serum 25-hydroxyvitamin D is inversely associated with body mass index in cancer.

BACKGROUND: The association between vitamin D deficiency and obesity in healthy populations and different disease states remains unsettled with studies reporting conflicting findings. Moreover, current dietary recommendations for vitamin D do not take into account a person's body mass index (BMI). We investigated the relationship between serum 25-hydroxy-vitamin D [25(OH)D] and BMI in cancer. METHODS: A consecutive case series of 738 cancer patients. Serum 25(OH)D was measured at presentation to the hospital. The cohort was divided into 4 BMI groups (underweight: <18.5, normal weight: 18.5-24.9, overweight: 25-29.9, and obese: >30.0 kg/m²). Mean 25(OH)D was compared across the 4 BMI groups using ANOVA. Linear regression was used to quantify the relationship between BMI and 25(OH)D. RESULTS: 303 were males and 435 females. Mean age at diagnosis was 55.6 years. The mean BMI was 27.9 kg/m² and mean serum 25(OH)D was 21.9 ng/ml. Most common cancers were lung (134), breast (131), colorectal (97), pancreas (86) and prostate (45). Obese patients had significantly lower serum 25(OH)D levels (17.9 ng/ml) as compared to normal weight (24.6 ng/ml) and overweight (22.8 ng/ml) patients; p < 0.001. After adjusting for age, every 1 kg/m² increase in BMI was significantly associated with 0.42 ng/ml decline in serum 25(OH)D levels. CONCLUSIONS: Obese cancer patients (BMI ≥ 30 kg/m²) had significantly lower levels of serum 25(OH)D as compared to non-obese patients (BMI <30 kg/m²). BMI should be taken into account when assessing a patient's vitamin D status and more aggressive vitamin D supplementation should be considered in obese cancer patients.

Role of nutritional status in predicting the length of stay in cancer: a systematic review of the epidemiological literature.

BACKGROUND: Length of stay (LOS) has been used as a surrogate marker for patients' well-being during hospital treatment. We systematically reviewed all pertinent literature on the role of nutritional status in predicting LOS in cancer. METHODS: A systematic search of human studies published in English was conducted using the MEDLINE data base (all articles published as of December 2010). We searched using the terms 'nutritional status' and 'nutritional assessment' and 'nutritional screening' and 'malnutrition' in combination with the following terms: length of stay, length of hospital stay, duration of stay, and duration of hospitalization together with 'cancer' or 'oncology'. RESULTS: The MEDLINE search identified a total of 149 articles, of which only 21 met the selection criteria. Of the 21 studies, 10 studies investigated gastrointestinal cancer patients, 4 gynecological cancer, and 7 heterogeneous cancer. Eight studies used subjective global assessment (SGA) or patient-generated SGA (PG-SGA), 9 used serum albumin and/or BMI, and 4 used other methods of nutritional assessment. CONCLUSIONS: Validated nutritional tools such as SGA/PG-SGA are better predictors of LOS in gastrointestinal cancers requiring surgery than in nonsurgical gastrointestinal cancer patients. Correcting malnutrition may decrease the LOS and perhaps even lower the rate of hospital readmissions in this population.

The prognostic role of quality of life assessment in breast cancer.

While the use of quality of life (QoL) assessments has been increasing in oncology, few studies have examined the prognostic significance of QoL in breast cancer. We investigated the association between QoL at presentation and survival in breast cancer. We examined 1,511 breast cancer patients treated at two single-system cancer centers between January 2001 and December 2008. QoL was evaluated using the validated survey instrument EORTC-QLQ-C30. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic significance of QoL after controlling for the effects of age, tumor stage, and prior treatment history. Mean age at presentation was 52.5 years. There were 590 analytic and 921 non-analytic patients. Patient stage of disease at diagnosis was I, 335; II, 591; III, 290; IV, 159; and 136 indeterminate. Median overall survival was 32.8 months (95% CI: 27.6-38.0). On univariate analysis, QoL function and symptom scales that were predictive of survival were physical (p < 0.001), role (p < 0.001), cognitive (p = 0.003), social (p < 0.001), fatigue (p < 0.001), nausea/vomiting (p < 0.001), pain (p < 0.001), dyspnea (p < 0.001), loss of appetite (p < 0.001), and constipation (p < 0.001). On multivariate analyses, only role function (degree of impairment of work and/or leisure/hobby related activities) was significantly associated with survival. This study suggests that baseline QoL (in particular, the role function) provides useful prognostic information in breast cancer.

Impact of oral vitamin D supplementation on serum 25-hydroxyvitamin D levels in oncology.

BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] is the major circulating form of vitamin D and a standard indicator of vitamin D status. Emerging evidence in the literature suggests a high prevalence of suboptimal vitamin D (as defined by serum 25(OH)D levels of <32 ng/ml) as well as an association between lower serum levels and higher mortality in cancer. We investigated the effect of oral vitamin D supplementation as a means for restoring suboptimal levels to optimal levels in cancer. METHODS: This is a retrospective observational study of 2198 cancer patients who had a baseline test prior to initiation of cancer therapy at our hospital to evaluate serum 25(OH)D levels between Jan 08 and Dec 09 as part of their initial nutritional evaluation. Patients with baseline levels of < = 32 ng/ml (n = 1651) were considered to have suboptimal serum 25(OH)D levels and were supplemented with 8000 IU of Vitamin D3 (four 2000 IU D3 capsules) daily as part of their nutritional care plan. The patients were retested at their first follow-up visit. Of 1651 patients, 799 were available for follow up assessment. The mean serum 25(OH)D levels were compared in these 799 patients across the 2 time points (baseline and first follow-up) using paired sample t-test. We also investigated the factors associated with response to vitamin D supplementation. RESULTS: Of 2198 patients, 814 were males and 1384 females. 1051 were newly diagnosed and treated at our hospital while 1147 were diagnosed and treated elsewhere. The mean age at presentation was 55.4 years. The most common cancer types were breast (500, 22.7%), lung (328, 14.9%), pancreas (214, 9.7%), colorectal (204, 9.3%) and prostate (185, 8.4%). The mean time duration between baseline and first follow-up assessment was 14.7 weeks (median 10.9 weeks and range 4 weeks to 97.1 weeks). The mean serum 25(OH)D levels were 19.1 ng/ml (SD = 7.5) and 36.2 ng/ml (SD = 17.1) at baseline and first follow-up respectively; p < 0.001. Patients with prostate and lung cancer had the highest percentage of responders (70% and 69.2% respectively) while those with colorectal and pancreas had the lowest (46.7% each). Similarly, patients with serum levels 20-32 ng/ml at baseline were most likely to attain levels > 32 ng/ml compared to patients with baseline levels < 20 ng/ml. CONCLUSIONS: The response to supplementation from suboptimal to optimal levels was greatest in patients with prostate and lung cancer as well as those with baseline levels between 20-32 ng/ml. Characteristics of non-responders as well as those who take longer to respond to supplementation need to be further studied and defined. Additionally, the impact of improved serum 25(OH)D levels on patient survival and quality of life needs to be investigated.

Optimizing innovation in health care organizations.

There are many steps to consider when making the move to become an innovative health care organization. Take a look at the people and processes to have in place.

Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy.

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR.

Aromatase inhibitors increase the sensitivity of human tumor cells to monocyte-mediated, antibody-dependent cellular cytotoxicity.

OBJECTIVE: A randomized, placebo-controlled phase III trial of the breast cancer vaccine Theratope (Biomira Corporation, Edmonton, Alberta, Canada), which expresses the underglycosylated, mucin-associated peptide STn showed that patients treated concomitantly with hormone therapy plus vaccine survived significantly longer than patients treated with hormone therapy plus a control vaccine. The objective of this study was to elucidate a mechanism to explain this effect. METHODS: Tumor cells characterized for expression of estrogen receptor (ER), STn, and Mucin-1 (Muc1) were pretreated (24 hours) with the aromatase inhibitor (AI) formestane, followed by assessment of sensitivity to monocyte-mediated killing in the presence and absence of STn or Muc1 antibodies (Abs) using the (51)Cr-release assay. RESULTS: ER+/STn+/Muc1+ tumor cells cultured in medium were equally sensitive to killing by monocytes in the absence or presence of STn and Muc1 Abs (mean = 54% and 55% cytolysis, respectively, P = not significant). Formestane-pretreated cells showed decreased sensitivity to killing by monocytes in the absence of Abs (mean = 45% cytolysis, P = .07) but significantly increased sensitivity to monocyte-mediated, antibody-dependent cellular cytotoxicity (MM-ADCC) (mean = 65%, P = .003). These effects were not seen with either ER+/STn-/Muc1+ cells or ER-/STn+/Muc1+ cells, indicating the need for both ER and STn positivity of the target tumor cells. CONCLUSIONS: Tumor cells treated with an AI exhibit increased sensitivity to MM-ADCC. The capacity of an AI to "sensitize" tumor cells to this form of antitumor immunity represents a heretofore, undescribed mechanism whereby a hormone-based treatment may collaborate with antigen-specific tumor immunity to produce improved tumor control in vivo in metastatic breast cancer patients.

Fatigue as a Driver of Overall Quality of Life in Cancer Patients.

BACKGROUND: This manuscript describes an approach for analyzing large amounts of disparate clinical data to elucidate the most impactful factor(s) that relate to a meaningful clinical outcome, in this case, the quality of life of cancer patients. The relationships between clinical and quality of life variables were evaluated using the EORTC QLQ-C30 global health domain--a validated surrogate variable for overall cancer patient well-being. METHODS: A cross-sectional study design was used to evaluate the determinants of global health in cancer patients who initiated treatment at two regional medical centers between January 2001 and December 2009. Variables analyzed included 15 EORTC QLQ-C30 scales, age at diagnosis, gender, newly diagnosed/ recurrent disease status, and stage. The decision tree algorithm, perhaps unfamiliar to practicing clinicians, evaluates the relative contribution of individual parameters in classifying a clinically meaningful functional endpoint, such as the global health of a patient. FINDINGS: Multiple patient characteristics were identified as important contributors. Fatigue, in particular, emerged as the most prevalent indicator of cancer patients' quality of life in 16/23 clinically relevant subsets. This analysis allowed results to be stated in a clinically-intuitive, rule set format using the language and quantities of the Quality of Life (QoL) tool itself. INTERPRETATION: By applying the classification algorithms to a large data set, identification of fatigue as a root factor in driving global health and overall QoL was revealed. The ability to practice mining of clinical data sets to uncover critical clinical insights that are immediately applicable to patient care practices is illustrated.

Modulation of tumor-infiltrating lymphocyte cytolytic activity against human non-small cell lung cancer.

The cytokines expressed in tumor microenvironments are thought to be important mediators of both the host immune response and tumor survival. The source of these cytokines includes tumor cells, infiltrating leukocytes, fibroblasts, and other stromal elements. We previously reported that tumor-infiltrating lymphocytes (TIL) from human non-small cell lung cancer (NSCLC) express predominantly type 1 cytokines, which are known to enhance cell-mediated immunity. The purpose of this study is to assess the cytokine mRNA expression of human NSCLC primary cell lines and the capacity of the tumor-associated cytokines to modulate the development of TIL cytolytic activity against the autologous tumor. Cytokine mRNA expression was determined by RT-PCR and the capacity of TIL to kill autologous lung tumor cells was measured by the chromium-51 (51Cr) release assay. All NSCLC primary cell lines expressed mRNA for IL-4, IL-6, and transforming growth factor-beta1 (TGFbeta1), whereas IL-10 was expressed in only 1/7 cell lines. When added to TIL cultures stimulated with anti-CD3+IL-2, IL-4 and IL-10 enhanced and TGF-beta1 suppressed the development of TIL cytolytic activity against autologous tumor cells. The effects of IL-6 were inconsistent and for the group, were not statistically significant. These results demonstrate that human NSCLC cells express cytokines with the capacity to regulate the in situ anti-tumor immune response. However, the effects of tumor-derived cytokines varied qualitatively and quantitatively suggesting the balance between specific type 2 cytokines or TGF-beta1 within tumor microenvironments may influence prognosis or response to immunotherapy.

Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis.

OBJECTIVE: To determine the effect of autologous peritoneal fluid and tumor necrosis factor-alpha (TNF-alpha) on proliferation of endometrial cells from women with endometriosis. DESIGN: Endometrial cells from eutopic and ectopic endometrium were cultured in vitro with peritoneal fluids or recombinant TNF-alpha for 72 hours before DNa synthesis determination by 3H-thymidine labeling and liquid scintillation counting. SETTING: An institute for the study and treatment of endometriosis and university-based research laboratories. PATIENT(S): Thirty-five women with endometriosis and 17 controls without endometriosis. MAIN OUTCOME MEASURE(S): In vitro incorporation of 3H-thymidine in endometrial cells was examined. RESULT(S): Peritoneal fluid from women with endometriosis enhanced proliferation of autologous and heterologous endometrial cell cultures from women with endometriosis. The soluble TNF-receptor etanercept blocked the ability of peritoneal fluid from women with endometriosis to enhance proliferation of eutopic or ectopic endometrial cells. Recombinant TNF-alpha also enhanced proliferation of eutopic and ectopic endometrial cells from women with endometriosis. In contrast, autologous peritoneal fluid, heterologous peritoneal fluid from women with endometriosis, and recombinant TNF-alpha failed to enhance, and often inhibited, the proliferation of eutopic endometrial cells from controls without endometriosis. CONCLUSION(S): Endometrial cells from women with endometriosis can utilize factors in peritoneal fluids, such as TNF-alpha, to facilitate proliferation in ectopic environments. Endometrial cells from women without endometriosis do not share this ability, suggesting that this abnormality is etiologically related to development of the disease. Therapy with agents that block the effects of TNF-alpha may be warranted.

Relationship between apoptosis and the number of macrophages in eutopic endometrium from women with and without endometriosis.

OBJECTIVE: To investigate the relationship between apoptotic cells and macrophages in the eutopic endometrium of women with and without endometriosis. DESIGN: Retrospective analysis of archival uterine endometrial biopsy specimens. SETTING: Institute for the Study and Treatment of Endometriosis, and university-based pathology and research laboratories. PATIENT(S): Fifty-one women with endometriosis and 24 healthy control subjects without endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The number of TUNEL+ (terminal deoxynucleotide transferase [TdT]-mediated deoxyuridine triphospate [dUTP] nick end-labeling-positive) (apoptotic) cells and CD68+ (CD68 positive) (macrophages). RESULT(S): Apoptotic cells and macrophage numbers were positively correlated in the eutopic endometrium of women with and without endometriosis. However, the number of apoptotic cells and the macrophage content in the endometrium of women with endometriosis was significantly reduced compared with that of healthy control subjects without endometriosis. Differences between apoptosis and macrophage numbers between the two populations were observed predominantly during the early proliferative phase of the menstrual cycle. CONCLUSION(S): The reduction in apoptosis described for endometrial cells in women with endometriosis may be related to reduced macrophage trafficking into the eutopic endomtrium during the early-proliferative phase of the menstrual cycle.

Immunology of endometriosis.

Endometriosis is a benign gynecologic disorder characterized by the ectopic growth of misplaced endometrial cells. A unifying hypothesis to explain endometriosis has not been elucidated as yet but numerous investigations have implicated disturbances in the immune response as fundamental to its etiology and pathogenesis. Clearly, the immune system is involved in endometriosis. It is not clear, however, whether and to what extent this involvement is a primary response leading to the initiation, promotion, and progression of the disease or a secondary response to the ectopic endometrial growth in an attempt to restore homeostasis. Thus, although numerous studies have shown alterations in cell-mediated and humoral immunity in subjects with endometriosis, the importance of these changes remains obscure. This review considers the past two decades of investigation of immune function changes in women with endometriosis with the expectation that this information will ultimately provide the basis for developing new approaches to patient management.

Resveratrol enhances mitomycin C-mediated suppression of human colorectal cancer cell proliferation by up-regulation of p21WAF1/CIP1.

BACKGROUND/AIM: Studies have shown that natural products could potentially be employed in combination therapies to decrease toxicity to healthy tissues by chemotherapy drugs. No studies however, have investigated the potential modulatory role of resveratrol (RV) on mitomycin C (MMC)-mediated effects on colorectal cancer. The aim of the present study was to investigate the impact of RV on MMC-mediated inhibition of colorectal cancer cell proliferation and to assess the potential mechanisms for such effects. MATERIALS AND METHODS: Primary cell lines generated from resected colorectal tumor specimens were treated with RV, MMC or RV+MMC and cell proliferation and gene expression analyses were performed. RESULTS: Suppression of cell proliferation by RV+MMC was significantly greater than individual treatments. RV+MMC synergistically modulated several genes but the up-regulation of p21(WAF1/CIP1) was several-fold greater. CONCLUSION: The up-regulation of p21(WAF1/CIP1), which inhibits the cell cycle at G0/G1 and G2/M phases, may represent the predominant mechanism for enhancement of MMC-mediated anti-cancer effects by resveratrol.